Exposure to stressful, psychosocial stimuli can lead to a variety of affective disorders, including depression, generalized anxiety disorder, and post-traumatic stress disorder. Serotonin is a key neurochemical signal that plays a pivotal role in the expression and treatment of stress-sensitive psychopathologies. In animal models, serotonin acts in several brain regions, including the basolateral amygdala (BLA), to regulate stress-induced changes in behavior indicative of anxiety and depression. In the current proposal, we will use a social defeat model in Syrian hamsters, called conditioned defeat, to investigate stress-induced changes in behavior within a psychosocial context. In our conditioned defeat model, social defeat results in a complete loss of species-typical territorial aggression and a substantial increase in submissive and defensive behavior when individuals are later tested with a smaller, non-aggressive opponent. In our working model, we propose that social defeat activates 5-HT neurons and that serotonin in turn modulates the formation of conditioned defeat by affecting key factors that regulate neural plasticity in the BLA such as cAMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF). More specifically, we propose that serotonin modulates the formation of conditioned defeat by acting at 5-HT1A receptors in the BLA to impair the CREB-BDNF pathway and acting at 5-HT2C receptors in the BLA to facilitate the CREB-BDNF pathway. In the current proposal we will test four predictions. First, we will test the prediction that injection of a 5-HT1A receptor antagonist into the BLA will enhance the acquisition and expression of conditioned defeat. Second, we will test the prediction that systemic administration of a 5-HT2C receptor agonist will enhance the acquisition and expression of conditioned defeat, and that the effects of the 5-HT2C receptor agonist will be blocked by injection of a 5-HT2C receptor antagonist into the BLA. Third, we will test the prediction that pharmacological activation of 5-HT1A autoreceptors in the dorsal raphe nucleus will block defeat-induced increases in phosphorylated CREB immunoreactivity within the BLA. Fourth, we will test the prediction that pharmacological activation of 5-HT1A autoreceptors in the dorsal raphe nucleus will block defeat-induced increases in BDNF mRNA expression within the BLA. PUBLIC HEALTH RELEVANCE: Exposure to stressful, psychosocial stimuli can lead to a variety of mood disorders, including major depression, generalized anxiety disorder, and post-traumatic stress disorder. In this proposal, we are investigating how neurochemical signals in select brain regions control the behavioral changes that occur following social defeat experience. Studying the neural mechanisms underlying defeat-induced changes in behavior should lead to a better understanding of stress-related psychopathologies, and ultimately to the development of better treatment options for these mental disorders.